For tissue repair or regeneration, cells must migrate into a wound bed, proliferate, express matrix components or form extracellular matrix, and form a final tissue shape. Multiple cell populations must often participate in this morphogenetic response, frequently including vascular and nerve cells. Matrices have been demonstrated to greatly enhance, and in some cases have been found to be essential, for this to occur. Natural cell in-growth matrices are subject to remodeling by cellular influences, all based on proteolysis, e.g. by plasmin (degrading fibrin) and matrix metalloproteinases (degrading collagen, elastin, etc.). Such degradation is highly localized and occurs only upon direct contact with the migrating cell. In addition, the delivery of specific cell signaling proteins such as growth factors is tightly regulated. In the natural model, macroporous cell in-growth matrices are not used, but rather microporous matrices that the cells can degrade, locally and upon demand, as the cells migrate into the matrix.
Controlled delivery devices for growth factors have been designed previously based on use of immobilized heparin to sequester the growth factor of some form. For example, Edelman et al. have used heparin-conjugated SEPHAROSE™ beads within alginate. The beads serve as reservoirs that release basic fibroblast growth factor (“bFGF”) slowly based on the binding and dissociation of bFGF with heparin.
It has been demonstrated that bi-domain peptides, which contain a factor XIIIa substrate sequence and a bioactive peptide sequence, can be cross-linked into fibrin gels and that this bioactive peptide retains its cellular activity in vitro (Schense, J. C., et al. (1999) Bioconj. Chem. 19:75-81). While peptides can partially mimic the bioactivity of the whole protein from which they are derived, this bioactivity is usually lower than the bioactivity of the whole protein, and sometimes it is impossible to mimic certain proteins with only a short peptide. It would therefore be desirable to be able to incorporate the entire protein, such as a growth factor or other pharmaceutically active molecule, into the matrix.
While delivery systems for proteins and growth factors exist and are known, there remains a need for a matrix for use in tissue repair that promotes cellular migration and tissue in-growth into the matrix through the control of growth factor presentation and release to the migrating cells and control of cellular adhesion sites. The need is particularly great for such in-growth matrices that could locally present growth factors and retain their influence and activity locally, through affinity interactions with the matrix, as occurs in nature.
It is therefore an object of the present invention to provide natural, biodegradable matrices for tissue repair, regeneration, and remodeling having incorporated therein growth factors which retain the activity of the intact growth factor molecules.
It is a further object of the present invention to provide natural, biodegradable matrices for controlled and/or sustained release of growth factors.